Abstract
Heart failure (HF) secondary to hypertensive heart disease typically presents as heart failure with preserved ejection fraction (HFPEF), which now accounts for nearly half of all HF diagnoses. HFPEF pathology is characterized by interstitial fibrosis leading to ventricular stiffness, diastolic dysfunction, and ultimately HF. Clinically HFPEF is a significant problem, as standard HF therapies, which target heart failure with reduced ejection fraction, are ineffective in HFPEF. A major challenge to developing new therapies for HFPEF is the lack of an animal model. In mice, although transverse aortic constriction (TAC) induces significant systolic dysfunction, it produces ventricular remodeling similar to chronic, untreated hypertension, which is associated with concentric hypertrophy, interstitial fibrosis, and diastolic dysfunction. Here, we examined pathologic remodeling and ventricular dysfunction following TAC in mice to determine what factors drive remodeling. TAC mice developed significant hypertrophy after 4 weeks (HW/BW, TAC: 7.2±0.4, n=13; Sham: 4.5±0.2, n=3; P<0.05 and Myocyte Area, TAC: 317±88μm2, n=13; Sham: 193±111μm2, n=3, P<0.05). However, TAC mice varied in extent of fibrotic response. Four mice showed minimal fibrotic response (1.47±0.28% of total ventricular area), five developed only perivascular fibrosis (6.87±1.02%), and four developed perivascular and interstitial fibrosis (29.95±5.81%). At four weeks post-surgery, TAC mice developed systolic dysfunction, indicated by reduced EF (TAC: 47±1%, n=13; Sham: 66±2%, n=3 P<0.05) and diastolic dysfunction, indicated by increased E/E’ (TAC: 44.9±4.5, n=13; Sham: 24.8±3.5, n=3; P<0.05). Interestingly, pathologic remodeling following TAC, both hypertrophy and fibrosis, correlated with E/E’ at week 4 (HW/BW: R2=0.343, P=0.036; Fibrosis: R2=0.517, P=0.008), but not EF (P=NS for both). The data suggest that pathologic remodeling following TAC was driven by diastolic dysfunction and interstitial fibrosis, not systolic dysfunction, indicating TAC induced HF might have more similarities to HFPEF than previously recognized.
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